title: Nicotine increases survival in human colon cancer cells treated with chemotherapeutic drugs.
abstract: Cigarette smoking is implicated in the development of colon cancer. Furthermore, nicotine increases cell proliferation and inhibits apoptosis through α7-nicotinic acetylcholine receptor (α7-nAChR) activation in human colon carcinoma cells. An open issue is whether nicotine interfere with colorectal cancer pharmacological treatment, by inhibiting drug-mediated apoptosis. To assess this hypothesis, we evaluated nicotine effect on Caco-2 and HCT-8 colon cancer cells, treated with 5-Fluorouracil (5-FU) and Camptothecin (CPT), chemotherapeutics commonly utilized as adjuvant treatment of colon cancer. Nicotine decreased anti-proliferative and pro-apoptotic effects exerted by chemotherapeutics on both cell lines. These effects partially reverted by exposure to α-bungarotoxin (α-BTX), an inhibitor of α7-nAChR. Nicotine addition to Caco-2 and HCT-8, treated with 5-FU or CPT, decreased the cleavage of substrate of caspase 3 and 7, poly-ADP-ribose polymerase (PARP). Moreover, P-ERK/ERK ratio was modified by nicotine addition to 5-FU and CPT treated cells in an opposite manner. However, when co-administrating PD98059, an ERK phosphorylation inhibitor, an increased apoptosis was observed. In Caco-2 and HCT-8 nicotine reverted 5-FU and CPT apoptotic effects through AKT phosphorylation, as demonstrated by apoptotic increase in presence of LY294002, an AKT phosphorylation inhibitor. Nicotine interfered with colorectal cancer pharmacological treatment in vitro by inhibiting apoptosis induced by chemotherapeutic drugs. Nicotine anti-apoptotic effects were exerted through ERK and AKT pathway activation.
authors.affiliation: Department of Clinical and Molecular Medicine, Sapienza University of Rome, Piazza Sassari 3, 00161 Rome, Italy; Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Via Antonio Scarpa 14, 00161 Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Dinicola
authors.forename: Veronica
authors.initials: V
authors.lastname: Morini
authors.forename: Pierpaolo
authors.initials: P
authors.lastname: Coluccia
authors.forename: Sara
authors.initials: S
authors.lastname: Proietti
authors.forename: Fabrizio
authors.initials: F
authors.lastname: D'Anselmi
authors.forename: Alessia
authors.initials: A
authors.lastname: Pasqualato
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Masiello
authors.forename: Alessandro
authors.initials: A
authors.lastname: Palombo
authors.forename: Giorgio
authors.initials: G
authors.lastname: De Toma
authors.forename: Mariano
authors.initials: M
authors.lastname: Bizzarri
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cucina
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D002166:Camptothecin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms; D004347:Drug Interactions; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D009538:Nicotine / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D005472:Fluorouracil; D002166:Camptothecin
keywords: 5-Fluorouracil; AKT; Apoptosis; Camptothecin; ERK; Nicotine